trans-acting eQTLs)71. 3). & Jernigan, T. L. The basics of brain development. By contrast, the adult cortical gene set was largely related to immune pathways. ADS Despite the existence of 15 genes in eQTL with ASD-associated SNPs in both fetal and adult cortical tissues, the majority of the changes in gene transcript levels were specific to either fetal (n=66), or adult (n=29) cortical tissue (Fig. Cell type- and differentiation-specific gene expression is precisely controlled by genomic non-coding regulatory elements (NCREs), which include promoters, enhancers, silencers and insulators. We functionally annotated the ASD-associated eQTLs to understand the potential regulatory mechanisms of the regions they tagged (Supplementary Table 5). Walker, R. L. et al. National Library of Medicine APOPT1, AS3MT) with the ASD-eQTL. https://doi.org/10.1038/s41598-021-95447-z, DOI: https://doi.org/10.1038/s41598-021-95447-z. Firstly, there was a significant enrichment of ASD-eQTLs within loci that are annotated as being regulated by PolyComb within the fetal, but not adult, cortex. Nat. Systematic identification of trans eQTLs as putative drivers of known disease associations. SF3B1 and THOC7 were also associated with ASD-eQTLs within the adult cortex. Synaptic Neurosci. Understanding the impact of SNPs associated with autism spectrum disorder on biological pathways in the human fetal and adult cortex. The GTEx eQTL discovery (https://github.com/broadinstitute/gtex-pipeline/tree/master/qtl) pipeline was further used to calculate normalized gene expression and covariates. Overall, our findings highlight potential regulatory mechanisms and pathways important for the etiology of ASD in early brain development and adulthood. Lancet 383, 896910 (2014). Biol. Correspondence to Google Scholar. & Pritchard, J. K. Cell 169, 11771186 (2017). Klei, L. et al. Res. 16, 469486 (2015). Scientific Reports (Sci Rep) Rau, S. et al. Article The number of shared items (e.g. Enh enhancers, Het heterochromatin, Quies quiescent/low, ReprPC repressed PolyComb, ReprPCWk week repressed PolyComb, TssA active TSS, TssAFlnk flanking active TSS, Tx strong transcription, TxWk weak transcription. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant and complex genetic etiology. Fetal and adult cortical tissue-specific PPI networks with immune and growth related phenotypes are affected by ASD-associated eQTLs. 193-e22B-3 (Academic Press, 2016). We incorporated cortex-specific expression patterns and PPI networks to identify candidate genes and pathways that have putative roles in the etiology of ASD-associated changes in the cortex. Genet. Google Scholar. Question: how could SNP's contribute to gene regulation? - Chegg An official website of the United States government. Genet. Furthermore, we constructed fetal and adult cortex-specific proteinprotein interaction networks and identified that ASD-associated regulatory SNPs impact on immune pathways, fatty acid metabolism, ribosome biogenesis, aminoacyl-tRNA biosynthesis and spliceosome in the fetal cortex. When SNPs occur within a gene or in a regulatory region near a gene, they may play a more direct role in disease by affecting the gene's function. SNPs may change the encoded amino acids (nonsynonymous) or can be silent (synonymous) or simply occur in the noncoding regions. A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450. Keller, R.) 89110 (Springer International Publishing, 2019). HLA-C and HLA-F; associated with endogenous antigen processing) and MHC class II (i.e. When present within a coding sequence and leading to an amino acid change (referred to as a non-synonymous SNP or mutation), they can modify the protein's activity. J. Mol. The Gene module within AutDB is a manually curated reference set of ASD-linked genes that was first released in 2007. Eleven genes (i.e. The author declares no competing interests. 2f). Tidsskr Nor Laegeforen. Enrichment analyses were performed using R package regioneR79 (permutation test: 1000). non-coding RNAs); (2) ASD is a spectrum disorder not a single highly characterised phenotype; and (3) like all polygenic disorders, ASD is likely to be a whole of body disorder with important etiological contributions from discrete and distant organs within the body. Would you like email updates of new search results? Weissbrod, O. et al. The authors would like to thank the Genomics and Systems Biology Group (Liggins Institute) for useful discussions. Psychiatry 10, 77 (2020). Again transcript levels for 12 genes are reduced. Imputed genotypes were filtered for HardyWeinberg equilibrium p<1106, variant missing genotype rate 0.05 and minor allele frequency 0.01. Genet. 42, 399403 (2017). Edges are only present if both interacting proteins are expressed in the cortical tissue. Gazal, S. et al. However, switching the ASD-eQTL to the minor allele is associated with an increase in transcript levels for these genes within the fetal cortex (Fig. 46, 881885 (2014). GWAS studies have identified genetic variants associated with ASD, but the functional impacts of these variants remain unknown. Molecular genetics of human pigmentation diversity. This will revolutionize the medical field in the future. . Identification of non-coding silencer elements and their regulation of Exploring the effects of genetic variation on gene regulation in cancer Of these genes, 15 are spatially regulated in both fetal and adult cortical tissues (Fig. By contrast, incorporating data on spatial chromatin organization (i.e. The main strength of this study is the integration of independent data sets, across distinct biological levels, that include cortex-specific 3D genome structure, eQTL and PPI data with ASD-associated GWAS SNPs. Slider with three articles shown per slide. Repeating similar analysis in other brain (e.g. J. Psychiatry 175, 359369 (2018). Abell, N. S. et al. Universit de Montral, Montreal, Quebec, Canada, Institut de Cardiologie de Montral, Montreal, Quebec, Canada, You can also search for this author in Phenotypes were defined as the mapped traits associated with the SNP in the GWAS Catalog. 2d). 8600 Rockville Pike Secondly, common SNPs only account for ~20% to the ASD risk6, suggesting that other genetic (e.g., rare variants, structural variation) and environmental factors also contribute to ASD etiology65,66. Cold Spring Harb. Won, H. et al. As such, the genes we identified need not directly overlap those that have been previously curated as being involved in ASD through deletion or mutation studies. Hormozdiari, F., Penn, O., Borenstein, E. & Eichler, E. E. The discovery of integrated gene networks for autism and related disorders. Moreover, this approach is not tissue or disease specific and is capable of identifying previously unknown tissue-specific contributions to ASD etiology and its interactions with multimorbid conditions. Notably, the significant difference (p=0.04531) in numbers of fetal cortical eQTLs, when compared to adult cortical eQTLs is consistent with a developmental origin for ASD risk. ADS Rev. Paternally inherited cis-regulatory structural variants are associated with autism. Genet. A common two-phase adipogenesis process is described: early determination and terminal differentiation phases, involving an intricate integration of cytoarchitecture, transcription factors and co-regulators, and signaling pathways. Genes regulated by Polycomb-repressed ASD-associated eQTLs in the fetal cortex. 3). RNA-seq data)20,21 were mapped to gene identifiers, thus there was a potential loss of data specificity, since genes typically produce multiple transcripts and protein variants due to alternative splicing. The significance of these associations in the developing cortex and how they contribute to the etiology of ASD remains to be empirically determined. For a specific TF-gene pair, detailed information could be observed in the rSNP report page using a link from the SNP in the 'element-gene-related SNPs . Genotypes (derived by Array Genotyping) for 219 fetal brain donors20 were downloaded from dbGaP (05/06/2020), processed and prepared in the GTEx format (Supplementary Fig. A. Sey, Benxia Hu, Hyejung Won, Anja Barei, Alexander Jolyon Nash, Boris Lenhard, Gokul Ramaswami, Hyejung Won, Daniel H. Geschwind, Michael J. Gandal, Jillian R. Haney, Daniel H. Geschwind, Mirolyuba Ilieva, Blanca Irene Aldana, Tanja Maria Michel, Jhih-Rong Lin, Yingjie Zhao, Zhengdong D. Zhang, Esra Sefik, Ryan H. Purcell, Jennifer G. Mulle, Scientific Reports *Gene transcript levels are associated with the same eQTL in both the fetal and adult cortical tissues. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. However, gene expression-based methods use an arbitrary definition of which genes contribute to the SNP enrichment score at each locus and either select a single gene with the highest cell type specific gene expression or include all the genes within the locus (Hu et al., 2011). What are single nucleotide polymorphisms (SNPs)? - MedlinePlus 2e). 1, Supplementary Fig. SNP selection and data report Bauer, D. E. et al. Single-nucleotide polymorphisms (SNPs) associated with ASD (n=454) were downloaded from the GWAS Catalog (www.ebi.ac.uk/gwas/; 05/04/2020; Supplementary Table 2). The same reference genome and annotation files were used to calculate expression for fetal brain RNA-seq data. Nat. Genet. Removal of HLA genes from analyses of the adult cortex gene set identified a retained enrichment for immune-related processes (e.g. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Nucleic Acids Res. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. 78, 4763 (2021). Hum Mol Genet. Thereby, SNPs contribute to disease susceptibility, various responses to medication treatment and differences in outcomes within a disease population [8, 9].